Where:
San Antonio, Texas

When:
Dec 8 - 11

The first research study presented in San Antonio was the fourth
adjuvant Herceptin trial to be presented in 2005, the BCIRG 006
study. As a part of NBCC's Clinical Trial Initiative, the protocol
for this trial is described in detail here:

www.stopbreastcancer.org/bin/index.asp?strid=457&btnid=1&de...

This three armed trial compared AC->T (Adriamycin+Cytoxan followed by
Taxotere) vs. AC->TH (Adriamycine+Cytoxan followed by
Taxotere+Herceptin) vs. TCH (Taxotere, Carboplatin, Herceptin) in
3,222 patients with HER2+ primary breast cancer. In this study, as
reported by Dennis Slamon, of UCLA, the hazard ratio in DFS (disease
free survival) of about half (0.49), in the AT->TH arm was comparable
to the results of the same regimen in the three already reported
trials at last May's ASCO. This means that only about half as many
patients had recurrences who got this regimen as in the AC->T arm,
during the follow-up period. The TCH arm also had statistically
significant reduction in recurrence, by comparison with the AC->T
arm, but the HR was 0.61, so this represents about a 40% improvement
in DFS. While they appear different, the two Herceptin-containing
arms do not show a statistically significant difference at this
point, so we can't know for sure which regimen is best.

Cardiotoxicity, the primary toxicity of concern with Herceptin, did
show a statistically significant difference between the arms,
however. As expected, the TCH arm had the least heart damage,
showing only 0.4% (less than half of one percent) of greater than 15%
loss in LVEF (left ventricular ejection fraction, a measure of heart
function). By contrast, the AC->TH arm showed a comparable loss in
2.4% of patients, a six-fold increase over the TCH results. The
third AC-->T arm, which contained Adriamycin, which is itself
cardiotoxic, showed an incidence of 0.6% (slightly more than half of
one percent). As the abstract stated, "There are fewer severe cardiac
adverse events when H is administered without prior A."

In his remarks on cardiotoxicity, Dr. Slamon made two important
additional points. First, he indicated that findings in the trial
indicate that the heart problems resulting from the combination of
Adriamycin and Herceptin treatment could be serious, and did not
prove to be reversible over 18 months, as had been previously
thought. Second, he found that a subset of HER2+ positive patients,
about 35%, also have amplification of a gene called topo II, which
makes them more likely to respond to Adriamycin, which targets topo
II. If confirmed, this may show that 65% of patients respond just as
well to the TCH regimen, which means that those who are co-amplified
with both HER2 and topo II might want to risk heart toxicity in
exchange for a better outcome.

More mature trial results await further analysis over time. The
abstract is below...

Musa

SABCS: ABSTRACT: [1] Phase III randomized trial comparing
doxorubicin and cyclophosphamide followed by docetaxel (AC T) with
doxorubicin and cyclophosphamide followed by docetaxel and
trastuzumab (AC TH) with docetaxel, carboplatin and trastuzumab (TCH)
in HER2 positive early breast cancer patients: BCIRG 006 study [San
Antonio Breast Cancer Symposium]

Background: This study evaluates the benefit of two trastuzumab-based
(H) regimens in HER2 amplified breast cancer with the intent of
integrating H to maximize efficacy and minimize known cardiotoxicity.

Material and Methods: HER2 amplified (centralized FISH) patients with
axillary lymph node (LN) positive or high risk LN negative were
randomized to either AC (60/600 mg/m2 q3wk x4) followed by T (100
mg/m2 q3wk x 4) or two H-containing regimens; AC followed by T with H
x 1 year (q1wk during chemo/q3wk during FUP) or TCarbo (75 mg/m2 /
AUC6 q3wk x 6) with H x 1 year. Patients were prospectively
stratified by positive LN (0, 1-3 vs 4+) and hormone receptor (HR)
status. Patients with HR+ tumors received hormonal therapy for 5 yrs
after chemotherapy. The primary endpoint was disease-free survival
(DFS) with 80% power (0.05 significance level) to detect an absolute
difference of 7%. Secondary endpoints included OS, safety, including
cardiotoxicity (symptomatic events -CHF, gr3/4 ischemia/infarction,
gr3/4 arrhythmia- and asymptomatic LVEF decline). We report the
results of the first planned, protocol-mandated interim analysis
conducted after 322 events (breast cancer relapse, second primary
malignancy or death).

Results: A total of 3222 pts (1073 in AC-T, 1074 in AC-TH and 1075 in
TCH) were recruited between Apr 2001 and Mar 2004. At a median
follow-up of 23 months, the two H-containing arms have both met the
DFS endpt: hazard ratio of 0.49 with AC-TH, p-value=0.00000048 and
0.61 with TCH, p-value=0.00015 (as compared to AC-T). At this time,
there is no statistically significant difference btw the two
H-containing arms perhaps due to the small number of events currently
separating them. Symptomatic cardiac events: AC-T: 1.2% vs AC-TH:
2.3%, p-value=0.046; AC-T vs TCH: 1.2%, p value=1.00. Absolute LVEF
decline >15% and below lower limit of normal occurred in 0.6% pts in
AC-T, 2.4% in AC-TH and 0.4% in TCH arms respectively (AC-T vs AC-TH
(p=0.001); AC-T vs TCH (p=0.54).

Discussion: Result of this trial confirms the benefit of H when
combined with docetaxel (AC-TH) or with docetaxel and carboplatin
(TCH) without an anthracycline. There are fewer severe cardiac
adverse events when H is administered without prior A. Longer
follow-up is needed in order to confirm whether non-A-based adjuvant
H regimens will have efficacy comparable to A-based regimens.